Most forms of cancer are derived from solid tumors (Shockley et al., Ann. N.Y. Acad. Sci. 1991, 617: 367–382), which have proven resistant in the clinic to therapies such as the use of monoclonal antibodies and immunotoxins. Anti-angiogenic therapy for the treatment of cancer was developed from the recognition that solid tumors require angiogenesis (i.e., new blood vessel formation) for sustained growth (Folkman, Ann. Surg. 1972, 175: 409–416; Folkman, Mol. Med. 1995, 1(2): 120–122; Folkman, Breast Cancer Res. Treat. 1995, 36(2): 109–118; Hanahan et al., Cell 1996, 86(3): 353–364). Efficacy of anti-angiogenic therapy in animal models has been demonstrated (Millauer et al., Cancer Res. 1996, 56:1615–1620; Borgstrom et al., Prostrate 1998, 35:1–10; Benjamin et al., J. Clin. Invest. 1999, 103: 159–165; Merajver et al., Proceedings of Special AACR Conference on Angiogenesis and Cancer 1998, Abstract #B-11, January 22–24). In the absence of angiogenesis, internal cell layers of solid tumors are inadequately nourished. Further, angiogenesis (i.e., aberrant vascularization) has been implicated in numerous other diseases (e.g., ocular neovascular disease, macular degeneration, rheumatoid arthritis, etc.). More recently, angiogenesis inhibition has been directly correlated with adipose tissue loss and weight loss in animal models, which suggests anti-angiogenic therapy may be useful in prevention of obesity (Rupnick et al., Proc. Natl. Acad. Sci. 2002, 99:10730–10735).
Contrastingly, normal tissue does not require angiogenesis except under specialized circumstances (e.g., wound repair, proliferation of the internal lining of the uterus during the menstrual cycle, etc.). Accordingly, a requirement for angiogenesis is a significant difference between tumor cells and normal tissue. Importantly, the dependency of tumor cells on angiogenesis, when compared to normal cells, is quantitatively greater than differences in cell replication and cell death, between normal tissue and tumor tissue, which are often exploited in cancer therapy.
Angiogenesis requires copper, as has been shown by numerous studies (Parke et al., Am. J. Pathol. 1988, 137:173–178; Raju et al., Natl. Cancer Inst. 1982, 69: 1183–1188; Ziche et al., Natl. Cancer Inst. 1982, 69: 475–482; Gullino, Anticancer Res. 1986, 6(2): 153–158). Attempts at preventing angiogenesis and hence tumor growth in animal models by reducing in vivo amounts of copper have been reported in the art (Brem et al., Neurosurgery 1990, 26:391–396; Brem et al., Am. J. Pathol. 1990, 137(5): 1121–1142; Yoshida et al., Neurosurgery 1995 37(2): 287–295). These approaches incorporated both copper chelators and low copper diets. More recently, Brewer et al., International Application No. PCT/US99/20374 have shown that the copper chelators, (e.g., tetrathiomolybdate) may be effective in treating diseases (e.g., solid tumor growth), which require angiogenesis.
In addition to the induction of angiogenesis, copper may also have a direct role in tumor cell growth and survival. High copper levels exist in both the plasma and in tumor tissue from patients with many different solid cancers (Chakravarty et al., J Cancer Res. Clin. Oncol. 1984, 108: 312–315). Recently, tetrathiomolybdate has been shown to down-regulate the expression of NF-κB as well as inhibit its translocation to the nucleus in the inflammatory breast cancer cell line SUM 149 (Pan et al., Cancer Res. 2002, 62: 4854–4859). The NF-κB system may be involved in mediating tumor cell survival and thus its down-regulation in tumor cells by tetrathiomolybdate suggests a direct effect of copper chelation on tumor survival.
Accordingly, novel thiomolybdate compounds, which are copper chelators, are required to fully explore the potential of copper chelators in treating and/or preventing angiogenesis and in tumor cell viability. Such novel thiomolybdate compounds may be effective in treating various diseases associated with angiogenesis such as cancer, copper metabolism disorders neurodegenerative disorders or obesity as well as treating diseases such as inflammatory disorders where the NF-κB pathway is dysregulated.